2-(4&#39; carboxy-butyl)-3:4-di(acylamido)-4:5 dihydrothiophene and its esters



Patented Jan. 25, 1949 ,2-(4' CARBOXY-BUTYL) 13:41? DRACYLAMI DO) 4:5DIHY R IQBHENE AN 4 'S,

S BS a Biotin is known to be one of the isomers'of the chemical compound2-(4 carboxy -butyl) -3:4- ureido-tetrahydrothiophene, having theempirical formula C1oH1sO3N2S, and'the structural formula: Y l M 1 It isnow found that this compound can be synthesized by reactions indicatedas follows:

Apiilication september 16'; 1944;. h I SerialNo. 554 ,454,- I

- sci ia 2 291 In the above formulae, R represents an alkyl, aryl orarylalkyl group; X, a halogen; and M an alkali metal or an alkalineearth metal.

The reactions above indicated are conducted as follows:2-amino-3-mercapto-propanoic acid (1) and chloroethanolc acid arecondensed in an alkaline aqueous solution to form2-amino-3-carboxymethylmercapto-propanoic acid (2); which is thentreated with an acylating agent, such as an acyl halide, in an aqueousalkaline solution to yield 2 acylamido 3oarboxymethylmercaptopropanoic'acid (3). 1 This product isesterifiedusing a mineral acid'catalyst to produce the diester (4) of the acid(3), and the diester is treated with alkali metal alcoholate or analkaline earth metal alcoholateto yield the'Z-alkali. metal or the2-"alkalinefieart'h' N metal derivative of an ester of2-carboxy-3-ketol-acylamido-tetrahydrothiophene (5). This compound, whenheated with-a dilute mineral acid, is hydrolyzed and decarboxylated toproduce 3-keto-4-acylamidotetrahydrothiophene (6) which, when reactedwith i4 -carboxybutanal ester in a lower aliphatic alcohol reactionmedium containing piperidine and a lower aliphatic carboxylic acid,produces 2-(4':- carboalkoxy butylidene) 3 keto 4-acylamidotetrahydrothiophene (7). This product, when reacted withhydroxylamine yields an esterof'the corresponding oxime,2-'(4'-carboxybutylldene) e 3- isonitroso 4 acyla'mido tetra-'hydrothiophene (8) which upon treatment with a mixture of zinc, alower'aliphaticacid and a lower aliphatic acid :anhydride, produces anequilibrium" mixture, of 2-(4'-carboxy-butylidene) -:3:4.-'di(acylamido). tetrahydrothiophen'e 'esiter (9a) andL2.(4Gcarboxy-butyl)-3:4- di( acylam'ido) '-4:5:dihydrothiophene ester(9b).;

3 This equilibriumimixture, or if :preferredsoue iii the equilibrants,is then treated 'wlth hydrogen in the presence of a hydrogenationcatalyst to yield 2- (4-carboxy-butyl) -3 :4-di(acylamido)tetrahydrothiophene ester 'Whenithisllast mentioned compound is treatedwith amaqueous alkaline solution, hydrolysis of the acyl groups occurs,yielding upon acidification, B-JQ KBBI boxy butyl) 3:4 diaminoxtetrahydrdthio- 4 'tipnsiiudicated above and idescribed Yin:concurrently filed applications Serial Nos. 5544455, 554,- .456 and554,457, into the vitamin biotin.

"Inasmuch as the 4-acy1amido substituent of the .istartingrmaterialiusedin practicing the process according to this invention remainsunaflfected by the process'wherein the products according to'.itlre;inveritioniarezubtained, it is evident that usualsimple-i4eacybamido'substituted compound of that phene (11) which,whenreactedwithra carbonyl no iii-we icambe u ff r example t e f w n nhalide, produces the compound -2-1-64knarhontybutyl) 3:4 ureidotetrahydrothiophene. product is obtained as a mixture of stereoisomers.one of which is racemic-biotin, from which upon resolution, is obtainedthe dextrorotatory isomer, biotin.

This invention is concerned with the intermediates numbered 9a and 91)above, namely 2- (4' carboxy butylidene) 3:4 adi(acy1amido)tetrahydrothiophenes and their equilibrants, 2- (4 carboxy butyl) 3:4-di(acy1amido) 4:5- dihydrothiophene,together withesters of each of theequilibrants represented bythe formulae:

of the eqiiilibrants lbyr-treating zan aestereof la ;2' 1

(4' -:carboxy -'.butylidene) ;3- 'isonitroso-- -a4-acylamidoatetrahydrothiophene :with zan'zanxtating-reducing :agent such:;as ;a zmixture iof ,ziumza lower aliphaticlacid and :a 'loweraliphatic acid anhydride whereby ithe s-isonitroso .:substituent issimultaneously reduced-by :znascent ihydroeen resulting from:interaction :of :.the :zinc rand the acid, and ,acylated :by the :acid:anhydride. Elie corresponding acids ;arercbtainedzfromathei estersbyssaponification followed by treatment with ran acid. V

.The :starting materials iused :in qirazcticing fiche process accordingto thisiinuention,-namlyrtlre esters of 42- (14' -lcarhoxy-T-hutylidene)ilmmiitrnso- 4-acylamido tetrahydrothiophene, can ibe slobtained :by thechemical'ereac'tions indicated above and -.described in detail inconcurrently ifilediapplications :Serial Nos. 554,458, $554,449, ,now228tenti2-,437;'T19,. 5514;450;554,451,3554352 anili554g453. .Iiheselequilibrants Scan Lbe :converted, mpera- :heaemployedin;the;presentprocess:

:2-(4 carboxy butylidene) 3 isonitroso 4---acetamfdo-tetrahydrothiophene esters 2-(4' carboxy butylidene) 3isonitroso 4- zpropanamidotetrahydrothiopheneesters 2 Q4'-- carboxybutyli'dene) --'-3 ison'itroso-M- ibenzamidotetrahydrothiophene esters.

Likewise lva riation .inrthe ester group idoesinotraf fect'materiall-ythe course ofrthereactionpmethyl, ethyl, gprqpyl, butyl, or other (lower.alkyl, and phenylglbenzyland other aryl .and arylalkyl esterscan;beased-satisfactorily.

The following example illustrates a methodoof carrying out the presentinvention, but it is to be understood that this example is given.by wayof illustration and not of limitation.

CuHsC 0 C1130 0 1 m NH 5 t om-sonxcrmio 02cm to aboutiroomstemperature.:Zinc particlesin the mixture are then removed, and thesolution isevaporated under diminished pressure to obtain a white residue. Thisresidue issuspended in water, warmed to about 50 C. to decompose anyremaining acetic anhydri'de, coo1ed and acidified tocongo withhydrochloric acid resulting in the precipitation of crude.2-(4-carbomethoxybutylidene) -3 -acetamido 4 benzamidotetrahydrothiophene (9a') together with its corresponding equilibrant;2-(4'-carbomethoxybrityll-S-acetamido -'4benzami'do-4:5-dihytirothiophene (91)). This crude product is removedand purified by known methods.

The crude mixture obtained as a product above comprises a mixture of twostereoisomeric racemates, whichwvheniractionally crystallized frommethanol yields a;first racemic mixture (M. P. -186 C.) correspondingto-F'ormulaQb above, and a relatively more soluble second racemicmixture -(M. P. 162-162? '0.) corresponding to Formula 9a above.

By .saponifying 2-.(4-ccarbomethcxyehutyl-r 8 idene) -3-acetamido 4benzamido tetrahydrothiophene or its equilibrant with warm alkali inaqueous alcohol, followed by acidification oigthe mixture, thecorresponding acid, 2-(4'-.carbo y-. butylidene) 3-acetamido- 4-benzamido tetrahydrothiophene or its equilibrant is obtained.

The first racemate when thus treated yields" a first racemio acidmixture (M. P. 177 0.); the

second racemate yields a second racemic acid mixture (M. P. 207 C.)

Modifications may be made in carrying out the present invention withoutdeparting from the- 4:5-dihydrothiophenes.

5. 2-(4"-oarboaralkoxy butyl) -3 4 di(acylamido) -4 S-dihydrothiophenes.

6. 2 (4'-carbomethoxy butyl) -3 :4; E di(acylamido)-4:5-dihydrothiophenes.

'1. 2-(4'-carbomethoxy-butyl)qa-acetamido-hbenzamido-4:B-dihydrothiophene.

8. Dihydrothiophene componnds having the formula:

RNH R'NH H- m-swm ooon" wherein R and R are acyl radicals and R" is aradical selected from the class which consislgs or hydrogen, alkyl,aryl, "and aralkyl radica STANTON A. GLEN E. ARTE.

REFERENCES cr'rEn The following references are of record in the file ofthis patent;

Whitmore Organic Chemistry" 1937; pages 187 and'l91.

